Browsing by Author "Millet, P"

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    Astrocytic TSPO upregulation appears before microglial TSPO in Alzheimer’s disease
    (IOS Press, 2020-06-30) Tournier, BB; Tsartsalis, S; Ceyzériat, K; Fraser, BH; Grégoire, MC; Kövari, E; Millet, P
    Background: In vivo PET/SPECT imaging of neuroinflammation is primarily based on the estimation of the 18 kDa-rranslocator-protein (TSPO). However, TSPO is expressed by different cell types which complicates the interpretation. Objective: The present study evaluates the cellular origin of TSPO alterations in Alzheimer’s disease (AD). Methods: The TSPO cell origin was evaluated by combining radioactive imaging approaches using the TSPO radiotracer [125I]CLINDE and fluorescence-activated cell sorting, in a rat model of AD (TgF344-AD) and in AD subjects. Results: In the hippocampus of TgF344-AD rats, TSPO overexpression not only concerns glial cells but the increase is visible at 12 and 24 months in astrocytes and only at 24 months in microglia. In the temporal cortex of AD subjects, TSPO upregulation involved only glial cells. However, the mechanism of this upregulation appears different with an increase in the number of TSPO binding sites per cell without cell proliferation in the rat, and a microglial cell population expansion with a constant number of binding sites per cell in human AD. Conclusion: These data indicate an earlier astrocyte intervention than microglia and that TSPO in AD probably is an exclusive marker of glial activity without interference from other TSPO-expressing cells. This observation indicates that the interpretation of TSPO imaging depends on the stage of the pathology, and highlights the particular role of astrocytes. © 2020 IOS Press and the authors. Open Access CC BY-NC 4.0
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    Fluorescence-activated cell sorting to reveal the cell origin of radioligand binding
    (SAGE, 2019-06-19) Tournier, BB; Tsartsalis, S; Ceyzériat, K; Medina, Z; Fraser, BH; Grégoire, MC; Kövari, E; Millet, P
    Many studies have explored the role of TSPO (18 kDa translocator protein) as a marker of neuroinflammation using single-photon emission computed tomography (SPECT) or positron emission tomography (PET). In vivo imaging does not allow to determine the cells in which TSPO is altered. We propose a methodology based on fluorescence-activated cell sorting to sort different cell types of radioligand-treated tissues. We compared left/right hippocampus of rats in response to a unilateral injection of lipopolysaccharide (LPS), ciliary neurotrophic factor (CNTF) or saline. We finally applied this methodology in human samples (Alzheimer's disease patients and controls). Our data show that the pattern of TSPO overexpression differs across animal models of acute neuroinflammation. LPS induces a microglial expansion and an increase in microglial TSPO binding. CNTF is associated with an increase in TSPO binding in microglia and astrocytes in association with an increase in the number of microglial binding sites per cell. In humans, we show that the increase in CLINDE binding in Alzheimer's disease concerns microglia and astrocytes in the presence of a microglial expansion. Thus, the cellular basis of TSPO overexpression is condition dependent, and alterations in TSPO binding found in PET/SPECT imaging studies cannot be attributed to particular cell types indiscriminately. © 2021 International Society for Cerebral Blood Flow and Metabolism
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    Knockout of TSPO delays and reduces amyloid, Tau, astrocytosis and behavioral dysfunctions in Alzheimer’s disease
    (Cold Spring Harbor Laboratory, 2022-03-28) Ceyzériat, K; Meyer, L; Boutjelda, F; Tsartsalis, S; Amossé, Q; Middleton, RJ; Liu, GJ; Banati, RB; Zilli, T; Garibotto, V; Millet, P; Tournier, BB
    The 18kDa translocator protein (TSPO) is up-regulated in glial cells in neurodegenerative diseases. In Alzheimer’s disease (AD) animal models, TSPO is first overexpressed in astrocytes and then in microglia. However, the precise role of TSPO in the onset and progression of pathology and symptoms characteristic of the disease remains unknown. Here, we report that in the absence of TSPO in 3xTgAD mice the expected disease onset is significantly delayed and a reduction is seen in the hippocampal load of poorly and highly aggregated forms of Tau (−44% and −82%, respectively) and Aβ42 (−25% and −95%, respectively), at 9 months of age. In addition, the astrocyte reactivity was decreased in 3xTgAD.TSPO−/− mice with a reduction in the morphologic complexity and the size of astrocytes in the dorso-dorsal hippocampus and the hilus. Functionally, the absence of TSPO ameliorated the cognitive consequences of adeno-associated virus-induced Tau over-expression in the hippocampus. This suggests that TSPO plays an important role in the active disease progression of AD. TSPO-inhibiting drugs thus merit further exploration as to their potential to reduce the rate of neurodegenerative disease progression. © 2022 The Authors
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    SPECT imaging of glioma with radioiodinated CLINDE: evidence from a mouse GL26 glioma model
    (Springer Nature, 2015-03-13) Tsartsalis, S; Dumas, N; Tournier, BB; Pham, TQ; Moulin-Sallanon, M; Grégoire, MC; Millet, P; Charnay, Y
    Recent research has demonstrated the potential of 18-kDa translocator protein (TSPO) to serve as a target for nuclear imaging of gliomas. The aim of this study was to evaluate SPECT imaging of GL26 mouse glioma using radioiodinated CLINDE, a TSPO-specific tracer. Methods GL26 cells, previously transfected with an enhanced green fluorescent protein (EGFP)-expressing lentivirus, were stereotactically implanted in the striatum of C57/Bl6 mice. At 4 weeks post-injection, dynamic SPECT scans with [123I]CLINDE were performed. A displacement study assessed specificity of tracer binding. SPECT images were compared to results of autoradiography, fluorescence microscopy, in situ nucleic acid hybridization, histology, and immunohistochemistry. Western blotting was performed to verify TSPO production by the tumor. Results Specific uptake of tracer by the tumor is observed with a high signal-to-noise ratio. Tracer uptake by the tumor is indeed 3.26 ± 0.32 times higher than that of the contralateral striatum, and 78% of the activity is displaceable by unlabeled CLINDE. Finally, TSPO is abundantly expressed by the GL26 cells. Conclusions The present study demonstrates the feasibility of [123I]CLINDE SPECT in translational studies and underlines its potential for clinical glioma SPECT imaging. © 2015, Springer Nature